Process for the preparation of baccatin III derivatives

ABSTRACT

A process for the preparation of 14 beta-hydroxy-1,4-carbonate-deacetylbaccatin III and intermediates useful for the preparation of novel taxan derivatives with antitumor activity are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is division of co-pending application Ser. No.10/343,991, filed on Feb. 6, 2003. Application Ser. No. 10/343,991 isthe national phase of PCT International Application No. PCT/EP01/08730filed on Jul. 27, 2001 under 35 U.S.C. § 371. The entire contents ofeach of the above-identified applications are hereby incorporated byreference.

The present invention relates to novel intermediates useful in thesynthesis of 14β-hydroxy-1,14-carbonate-deacetylbaccatin IIIderivatives, and to a process for the preparation thereof. Theintermediates obtained with the process of the invention can be used inthe preparation of novel taxan derivatives with antitumor activity.

Taxanes are one of the most important classes of antitumor agentsdeveloped in recent years. Paclitaxel is a complex diterpene isolatedfrom the bark of Taxus brevifolia and is considered a “lead compound”for cancer therapy. Extensive research is at present being carried outfor taxan derivatives having higher pharmacological activity andimproved pharmacokinetic profile. A particular approach relates to thebaccatin III derivatives variously modified with respect to the basicstructure. Examples of said compounds are the 14β-hydroxy baccatin IIIderivatives disclosed in U.S. Pat. No. 5,705,508, WO 97/43291, WO96/36622. At present, 14β-hydroxy-1,14-carbonate-deacetylbaccatin IIIderivatives are prepared starting from the 14β-hydroxy-deacetylbaccatinIII precursor, which is a natural compound obtainable in small amountsby extraction of leaves of Taxus wallichiana, as disclosed in EP559,019. There is strong need for novel intermediates or alternativeprocesses to those commonly used, which allow to prepare14β-hydroxy-1,14-carbonate-deacetylbaccatin III derivatives simply andeffectively.

It has now been found that 14β-hydroxy-1,14-carbonate-deacetylbaccatinIII can be prepared by means of a process using 10-deacetylbaccatin IIIas starting compound which, contrary to 14β-hydroxy-baccatin III, can beeasily isolated in large amounts form Taxus baccata leaves.

Therefore, the present invention provides a process for the preparationof 14β-hydroxy-1,14-carbonate-deacetylbaccatin III comprising thefollowing steps:

-   -   1. protection of the hydroxy groups at the positions 7 and 10 of        10 deacetylbaccatin III:        wherein R and R₁ are selected from hydrogen, C₁-C₁₀ alkyl or        aryl, C₁-C₁₀ alkyl- or aryl-carbonyl, trichloroacetyl, C₁-C₄        trialkylsilyl; preferably, when R and R₁ are the same, they are        trichloroacetyl, whereas when they are different, preferably R        is trichloroacetyl and R₁ is acetyl, or R is triethyl or        trimethylsilyl and R₁ is acetyl;    -   2. two-step oxidation to give the derivative oxidised at the        13-position and hydroxylated at the 14-position:    -   3. carbonation of the vicinal hydroxyls at the 1- and        14-positions to give the 1,14-carbonate derivative:    -   4. reduction of the carbonyl at the 13-position:    -   5. removal of the protective groups at the 7- and 10-positions:

The procedures for the protection of the 7- and 10-hydroxyls aredescribed by Holton et al., Tetrahedron Letters 39, (1998) 2883-2886.The selective protection of the hydroxyls of the starting compounddeacetylbaccatin III is possible due to their different reactivity. Inparticular, the reactivity towards acylating, alkylating or silylatingagents has been found to vary in the orderC(7)-OH>C(10)-OH>C(13)-OH>C(1)-OH, therefore the

groups at 7- and 10- can be selectively protected while keeping thehydroxyls at 1- and 13- free. Furthermore, by changing the reactionconditions, it is possible to reverse the reactivity order of thehydroxyls at 7- and 10- thus allowing the differential substitutionthereof. Examples of reactants and reaction conditions usable in theprotection of the hydroxyls at 10- and 7- are reported in the abovecited publication.

The oxidation step of the hydroxyl at the 13-position is achieved withmanganese dioxide or bismuth dioxide in a solvent selected fromacetonitrile, acetone or ethyl acetate/methylene chloride 9:1 mixtures,under vigorous stirring, preferably with manganese dioxide inacetonitrile or acetone. The reaction proceeds quickly to give theoxidised derivative at the 13-position, which can be recovered from thereaction medium, whereas a longer reaction yields the 13-oxidised and14-hydroxylated derivative.

The subsequent carbonation step of the hydroxyls at the 1- and14-positions is usually effected with phosgene or triphosgene in amethylene chloride/toluene mixture in the presence of pyridine.Subsequently, the resulting 1,14-carbonate derivative can be easilyreduced at the 13-position to give the corresponding 13-hydroxyderivative. Said reduction takes place regioselectively on the carbonylat 13- while the carbonyl at 9- remains unchanged, andstereoselectively, affording almost exclusively the 13-α isomer. Thisreaction is usually carried out with sodium borohydride in methanol andprovides high yields. The last step consists in deprotecting thehydroxyls at the 7- and 10-positions to give the final product14β-hydroxy-1,14-carbonate deacetylbaccatin III. The conditions and thereactants which can be used in the selective deprotection of thehydroxyls at 7- and 10- are described in Zheng et al., TetrahedronLett., 1995, 36, 2001, and in Datta et al., J. Org. Chem., 1995, 60,761. The resulting final product is an extremely useful intermediate forthe synthesis of a variety of taxan derivatives. As mentioned above,said intermediate was prepared until now starting from 14β-hydroxybaccatin III extracted from the leaves of Taxus wallichiana in lowyields. The process of the present invention allows to prepare the sameintermediate in high yields starting from a compound available in largeamounts. Examples of compounds with antitumor activity which can beprepared starting from 14β-hydroxy-1,14-carbonate deacetylbaccatin IIIare reported in U.S. Pat. No. 5,705,508, WO 97/43291, WO 96/36622.

According to a preferred embodiment of the process of the invention,deacetylbaccatin III is reacted with trichloroacetyl chloride inmethylene chloride in the presence of triethylamine and usingN,N-dimethylaminopyridine (DMAP) in catalytic amounts. The use oftrichloroacetate as protecting group proved to be very advantageous inthe oxidation, carbonation and reduction steps according to the processof the invention. In particular, the 7,10-bis-trichloroacetatederivative, which is obtained in quantitative yields from the startingcompound, after oxidation and carbonation is easily reduced at the13-position with simultaneous deprotection of the trichloroacetic groupsto give 14β-hydroxy-1,14-carbonate-deacetylbaccatin III. The use of DMAPin catalytic amounts provides definite advantages from the industrialand environmental point of views, when considering that until now theacylations of this substrate were carried out in pyridine withconsequent discharge problems of the residual solvent.

The following intermediates obtained according to the preferredembodiment described above are part of the present invention:

The following examples illustrate the invention in greater detail.

EXAMPLE I Preparation of 7,10-bistrichloroacetyl-10-deacetylbaccatin III

First Alternative:

4.77 ml of trichloroacetic anhydride (42.32 mmol) is added by drops to asolution of 10 g of 10-deacetylbaccatin III (18.4 mmol) in 125 ml of drymethylene chloride and 42 ml of pyridine. The reaction mixture is keptunder stirring for three hours or anyway until completion of thereaction, checking by TLC on silica gel using as eluent ann-hexane/ethyl acetate 1:1 mixture. After completion of the reaction, 5ml of methanol are added to destroy the excess of trichloroaceticanhydride, then water is added. The organic phase is thoroughly washedwith acidic water (HCl) to remove pyridine, whereas the remainingorganic phase is dried over MgSO4 and concentrated to dryness undervacuum, to obtain a pale yellow solid (17 g) which is crystallised fromchloroform: [α]_(D) −34° (CH₂Cl₂ C5.8) IR (KBr) 3517, 1771, 1728, 1240,981, 819, 787, 675 cm⁻¹;

¹H-NMR (200MH): δ 8.11 (Bz C), 7.46 (Bz, BB′), 6.50 (s, H-10), 5.72 (m,H-7 H-29, 5.02 (d, J=8 Hz, H-5), 4.95 8m, H-13), 4.37 (d, J=8 Hz,H-20a), 4.18 (d, J=8 Hz, H-20b), 4.02 (d, J=6 Hz, H-3), 2.32 (s, 4-Ac),2.22 (s, H-18), 1.91 (s, H-19), 1.25 and 1.11 (s, H-16, H-17), 1.94 (m,H 14α), 1.89 (m, H14β).

Second Alternative:

10-deacetilbaccatin III (10 g, 18.38 mmol) is suspended in CH₂Cl₂ (120ml), added with DMAP (220 mg, 1.4 mmol, 0.1 eqv.) and cooled to 0° C. onice bath. Et₃N (10.26 ml, 73.6 mmol, 4 eqv.) and immediately after,Cl₃CCOCl (4.12 ml, 36.8 mmol, 2 eqv.) are added under nitrogen stream in5 min, keeping the temperature under 10° C. After completion of theaddition, the mixture is left under stirring on ice bath for 15 min,then the bath is removed and the reaction stirred at room temperaturefor 1 h. After 1 h the reaction is checked by TLC (AcOEt 2/n-hexane 3,Rf 10-DAB III=0.05, Rf 7,10-bistrichloroacetyl-10-DAB III=0.26) andadded with Cl₃CCOCl (1 ml, 0.5 eqv.). Stirring is continued at r.t. for10 min, then the reaction is poured into a beaker containing 160 g oftriturated ice and left under stirring until equilibrium at r.t. (about1 h). The aqueous phase is then separated and extracted with CH₂Cl₂(3×40 ml). The combined organic phases are washed with 1N HCl (20 ml),then with a NaHCO₃ saturated solution (20 ml), dried over Na₂SO₄ and thesolvent is evaporated off. Crude weight: 16.5 g. After crystallisationfrom chloroform, the IR, ¹H-NMR and [α]_(D) spectra are consistent withthose of the compound obtained using pyridine and trichloroaceticanhydride.

EXAMPLE II Oxidation at 13- and hydroxylation at 14- of7,10-bistrichloroacetate 10-deacetylbaccatin III

30 g of activated MnO₂ are added to a solution of 10-deacetylbaccatinIII 7,10-bistrichloroacetate (3 g) in acetonitrile (40 ml), stirring thesuspension with magnetic stirrer at room temperature and monitoring theprogress of the reaction by TLC (petroleum ether-ethyl acetate 5:5; Rfof the starting material about 0.31). After about one hour, theformation of the 13-dehydroderivative is completed (TLC analysis, Rf ofthe 13-dehydroderivative about 0.50). Stirring is then continued forabout 72 hours, during which time the 13-dehydroderivative is slowlyoxidised to the corresponding 14β-hydroxy derivative (Rf about 0.36).The reaction mixture is filtered through Celite, and the cake isrepeatedly washed with ethyl acetate. The solvent is evaporated off andthe residue is purified by column chromatography on silica gel (100 ml,eluent petroleum ether-ethyl acetate 7:3) to obtain 170 mg of the13-dehydroderivative and 2.38 g of the 14β-hydroxy-13-dehydroderivative.

13-dehydro-14-hydroxy-10-deacetylbaccatin III, 7,10-bistrichloroacetate: white powder, m.p. 97° C.; IR (KBr disc): 3440, 1780,1767, 1736, 1686, 1267, 1232, 1103, 1010, 854 cm⁻¹;

¹H-NMR (200 MHz, CDCl₃): δ 8.07 (Bz AA′), 7.60 (Bz, C), 7.49 (Bz, BB′),6.52 (s, H-10), 5.92 (d, J=6.7 Hz, H-2), 5.70 (br t, J=8.0 Hz, H-7),4.95 (br d, J=8.2 Hz, H-5), 4.37 (d, J=8.2 Hz, H-20a), 4.31 (d, J=8.2Hz, H-20b), 4.17 (s, H14), 4.02 (d, J=6.7 Hz, H-3), 2.71 (m, H-6), 2.29(s, OAc), 2.17 (s, OAc), 1.96 (s, H-18), 1.27, 1.01 (s, H-16, H-17 andH-19).

EXAMPLE III Oxidation/hydroxylation of 7-triethylsilylbaccatin III

10 g of activated MnO₂ are added to a solution of7-triethylsilylbaccatin III (1.0 g) in acetonitrile (10 ml), stirringthe suspension with magnetic stirrer at room temperature and monitoringthe progress of the reaction by TLC (petroleum ether-ethyl acetate 6:4;Rf of the starting material about 0.25). After about two hours, theformation of the 13-dehydroderivative is completed (TLC analysis, Rf ofthe 13-dehydroderivative about 0.45). Stirring is then continued forabout 188 hours, during which time further MnO₂ (10 g) is added. The13-dehydroderivative is slowly oxidised to the corresponding 14β-hydroxyderivative (Rf about 0.38). The reaction mixture is filtered throughCelite, and the cake is washed with ethyl acetate. The solvent isevaporated off and the residue is purified by column chromatography onsilica gel (40 ml, eluent petroleum ether-ethyl acetate 7:3) to obtain126 mg of the 13-dehydroderivative, 479 mg (46%) of the14β-hydroxy-13-dehydroderivative and 189 mg of a mixture of both.

13-Dehydro-7-triethylsilylbaccatin III, white powder, m.p. 168° C.[α]_(D) ²⁵ −35 (CH₂Cl₂, C 0.67) IR (KBr) 3488, 1726, 1711, 1676, 1373,1269, 1244, 1230, 1105 cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 8.07 (Bz AA′), 7.60(Bz, C), 7.49 (Bz, BB′), 6.59 (s, H-10), 5.69 (d, J=6.9 Hz, H-2), 4.92(d, J=8.2 Hz, H-5), 4.48 (dd, J=10.6 Hz, H-7), 4.33 (d, J=8.0 Hz,H-20a), 4.12 (d, J=8.0 Hz, H-20b), 3.91, (d, J=6.9 Hz, H-3), 2.96 (d,J=20 Hz, H-14a), 2.65 (d, J=20 Hz, H-20b), 2.50 (m, H-6α), 2.23 (s,OAc), 2.19 (s, OAc+H-18), 1.67, 1.28, 1.19 (s, H-16, H-17 and H-19),0.19 (m, TES).

13-Dehydro-14β-hydroxy-10-deacetylbaccatin III, 7,10-bistrichloroacetate: white powder, m.p. 153° C. [α]_(D) ²⁵ +20 (CH₂Cl₂, C0.75) IR (KBr) 3431, 1723, 1692, 1371, 1269, 1242, 1223, 1096 cm⁻¹;¹H-NMR (500MH CDCl₃): δ 8.06 (Bz AA′), 7.60 (Bz, C), 7.48 (Bz, BB′),6.51 (s, H-10), 5.88 (d, J=6.9 Hz, H-2), 4.90 (d, J=8.2 Hz, H-5), 4.47(dd, J=10.67 Hz, H-7), 4.30 (d, J=8 Hz, H-20a), 4.28 (d, J=8.2 Hz,H-20b), 4.13 (br d, J=2 Hz, H-14), 3.84 (d, J=6.9 Hz, H-3), 3.69 (br d,J=2 Hz, 14-OH), 3.62 (s, 1-OH), 2.52 (m, H-6α), 2.24 (s, OAc), 2.21 (s,OAc), 2.11 (s, H-18), 1.92 (m, H-6β), 1.74, 1.56, 1.28 (s, -h-16, H-17and H-19), 0.94 (m, TES), 0.59 (m, TES). HRNS: 714.3092 (calculated forC₃₇H₅₀O₁₂Si 714.3092).

EXAMPLE IV Oxidation/hydroxylation of 7-triethylsilylbaccatin III

10 g of activated MnO₂ are added to a solution of7-triethylsilylbaccatin III (1.0 g) in acetonitrile (10 ml), withstirring at room temperature and monitoring the progress of the reactionby TLC (petroleum ether-ethyl acetate 6:4; Rf of the starting materialabout 0.25). After about two hours, the formation of the13-dehydroderivative is completed (TLC analysis, Rf of the13-dehydroderivative about 0.45). Stirring is then continued for about188 hours, during which time further MnO₂ (10 g) is added. The13-dehydroderivative is slowly oxidised to the corresponding 14β-hydroxyderivative (Rf about 0.38). The reaction mixture is filtered throughCelite, and the cake is washed with ethyl acetate. The solvent isevaporated off and the residue is purified by column chromatography onsilica gel (40 ml, eluent petroleum ether-ethyl acetate 7:3) to obtain126 mg of the 13-dehydroderivative, 479 mg (46%) of the14β-hydroxy-13-dehydroderivative and 189 mg of a mixture of both.

13-Dehydro-7-triethylsilylbaccatin III. white powder, m.p. 210° C.[α]_(D) ²⁵ −48 (CH₂Cl₂, C 0.50) IR (KBr) 3478, 1728, 1676, 1373, 1271,1240, 1071, 1026 cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 8.07 (Bz AA′), 7.64 (Bz,C), 7.50 (Bz, BB′), 6.46 (s, H-10), 5.70 (d, J=6.9 Hz, H-2), 4.95 (d,J=8.2 Hz, H-5), 4.51 (dd, J=10.7 Hz, H-7), 4.32 (d, J=8.4 Hz, H-20a),4.14 (d, J=8.4 Hz, H-20b), 3.92, (d, J=6.9 Hz, H-3), 2.99 (d, J=20 Hz,H-14a), 2.68 (d, J=20 Hz, H-14b), 2.56 (m, H-6α), 2.29 (s, OAc), 2.18(s, OAc), 2.08 (s, H-18), 1.68, 1.29, 1.20 (s, H-16, H-17 and H-19),0.19.

13-Dehydro-14β-hydroxy-7-triethylsilylbaccatin III: white powder, m.p.220° C. [α]_(D) ²⁵+19 (CH₂Cl₂, C 0.42) IR (KBr) 3568, 1710, 1719, 1686,1372, 1282, 1240, 1219, 1073 cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 8.09 (BzAA′), 7.60 (Bz, C), 7.51 (Bz, BB′), 6.39 (s, H-10), 5.89 (d, J=6.9 Hz,H-2), 4.94 (d, J=8.2 Hz, H-5), 4.47 (dd, J=10.7 Hz, H-7), 4.31 (br s,—H-20a+H-20b), 4.15 (s, H-14), 3.69 (d, J=6.9 Hz, H-3), 2.29 (s, OAc),2.16 (s, H-18), 2.14 (s, OAc), 1.74, 1.21, 1.10 (s, H-16, H-17 andH-19), HRMS: 600.6112 0.19 (calculated for C₃₁H₃₆O₁₂Si 600.6103).

EXAMPLE V Preparation of 1,14-carbonate-13-dehydro-7-tes-baccatin III

A solution of 13-dehydro-14β-hydroxy-7-triethylsilylbaccatin III (124mg, 1.17 mMol) in CH₂Cl₂ (1 ml) and pyridine (0.56 ml, 6.8 mMol, 20 mol.equiv.) is added drop by drop in 5 min to a solution of phosgene (1.8 mlof a 20% solution in toluene, 3.4 mMol, 20 mol. equiv.) in CH₂Cl₂ (2ml). The mixture is stirred at room temperature for 1 hour andsubsequently the excess of phosgene is neutralised with a NaHCO₃saturated solution and extracted with CH₂Cl₂. The organic phase iswashed with a NaHCO₃ saturated solution, brine, and dried (Na₂SO₄). Thesolvent is evaporated off to yield a reddish residue, which is purifiedon a small silica gel column (about 5 ml, eluent hexane/ethyl acetate8:2) to obtain 118 mg (92%) of the carbonate. When the reaction iscarried out with triethylamine as base without the reverse addition,mixture of 1,14-carbonate and 2-debenzoyl-1,2-carbonate-14 benzoate(about 1:15) is obtained.

13-Dehydro-14β-hydroxy-7-triethylsilylbaccatin III 1,14-carbonate, whitepowder, m.p. 153° C. [α]_(D) ²⁵+23 (CH₂Cl₂, C 0.75) IR (KBr) No. of bandOH 1834, 1734, 1709, 1373, 1242, 1225, 1088, 1057 cm⁻¹; ¹H-NMR (200MHCDCl₃): δ 7.99 (Bz AA′), 7.60 (Bz, C), 7.48 (Bz, BB′), 6.51 (s, H-10),6.12 (d, J=6.9 Hz, H-2), 4.90 (d, J=8.2 Hz, H-5), 4.78 (s, H-14), 4.44(dd, J=10.7 Hz, H-7), 4.34 (d, J=8 Hz, H-20a), 4.19 (d, J=8.2 Hz,H-20b), 3.80 (d, J=6.9 Hz, H-3), 2.50 (m, H-6α), 2.23 (s, OAc), 2.22 (s,OAc), 2.19 (s, H-18), 1.92 (m, H-6β), 1.72, 1.39, 1.26 (s, —H-16, H-17and H-19), 0.90 (m, TES), 0.56 (m, TES). HRNS: 740.2851 (calculated forC₃₈H₄₈O₁₃Si 740.2864).

13-Dehydro-14β-hydroxybaccatin III 1,14-carbonate, white powder 240° C.[α]_(D) ²⁵−2.5 (CH₂Cl₂, C 0.4) IR (KBr) 3539, 1831, 1736, 1240, 1088,1068, 1057, 1024 cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 7.98 (Bz AA′), 7.61 (Bz,C), 7.50 (Bz, BB′), 6.39 (s, H-10), 6.14 (d, J=6.9 Hz, H-2), 4.98 (d,J=8.2 Hz, H-5), 4.80 (s, H-14), 4.43 (dd, J=10.7 Hz, H-7), 4.35 (d, J=8Hz, H-20a), 4.24 (d, J=8.2 Hz, H-20b), 3.80 (d, J=6.9 Hz, H-3), 2.50 (m,H-6α), 2.30 (s, OAc), 2.20 (s, OAc), 2.15 (s, H-18), 1.90 (m, H-6β),1.74, 1.34, 1.25 (s, H-16, H-17 and H-19), HRMS: 626.2005 (calculatedfor C₃₃H₃₄O₁ 626.1999).

EXAMPLE VI Preparation of 1,14-carbonate-7-O-triethylsilyl baccatin III

An excess of NaBH₄ (about 20 mg) is added in small portions to asolution of 13-dehydro-14β-hydroxy-7-triethylsilylbaccatin III1,14-carbonate (50 mg) in methanol (5 ml). After 30 min., the reactionmixture is added with saturated NH₄Cl, extracted with ethyl acetate,washed with brine, dried over Na₂SO₄ and the solvent is removed, to givea residue which is purified by column chromatography in silica gel(about 5 ml, elution with hexane-ethyl acetate 8:2) to obtain 35 mg ofthe 13α-hydroxy derivative and 9 mg of the 13β-hydroxy derivative.

14β-Hydroxy-7-triethylsilylbaccatin III 1,14-carbonate [α]_(D) ²⁵−35(CH₂Cl₂, C 0.60) IR (KBr) 3054, 1819, 1736, 1603, 1371, 1261, 1238,1090, 1069, cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 8.06 (Bz AA′), 7.65 (Bz, C),7.50 (Bz, BB′), 6.47 (s, H-10), 6.12 (d, J=6.9 Hz, H-2), 5.05 (br d,J=5.5 Hz, H-13), 4.98 (br d, J=9 Hz, H-5), 4.83 (d, J=5 Hz, H-14), 4.50(dd, J=10.7 Hz, H-7), 4.34 (d, J=6α), 2.34 (s, OAc), 2.22 (s, OAc), 1.78(m, H-6β), 1.35 (s, H-18), 1.75, 1.18, 0.95 (s, —H-16, H-17 and H-19),0.90 (m, TES), 0.62 (m, TES).

14β-Hydroxy-7-triethylsilyl-13-epibaccatin III 1,14-carbonate, amorphous[α]_(D) ²⁵−13 (CH₂Cl₂, C 0.60) IR (KBr) 3630, 1825, 1734, 1603, 1375,1262, 1091, 1071, 1049 cm⁻¹; ¹H-NMR (200MH CDCl₃): δ 8.01 (Bz AA′), 7.63(Bz, C), 7.48 (Bz, BB′), 6.44 (s, H-10), 6.12 (d, J=7.2 Hz, H-2), 4.90(br d, J=9 Hz, H-5), 4.81 (d, J=8 Hz, H-14), 4.48 (br, J=8, H-13), 4.50(dd, J=10, 7 Hz, H-7), 4.41 (d, J=8 Hz, H-20a), 4.31 (d, J=8 Hz, H-20b),3.68 (d, J=7.2 Hz, H-3), 2.60 (m, H-6α), 2.32 (s, OAc), 2.26 (s, H-18),2.21 (s, OAc), 1.80 (m, H-6β), 1.72, 1.43, 1.27 (s, —H-16, H-17 andH-19), 0.93 (m, TES), 0.61 (m, TES).

EXAMPLE VII Preparation of13-dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatin III1,14-carbonate

A solution of 13-dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatinIII (200 mg) in CH₂Cl₂ (2 ml) and pyridine (1.12 ml, 20 equiv.) is addedin 5 min with a solution of phosgene (20% in toluene, 3.6 ml, 20 equiv.)in CH₂Cl₂ (2 ml). The mixture is stirred at r.t. for 1 h, then theexcess of phosgene is neutralised with a NaHCO₃ saturated solution (3ml). The mixture is extracted with CH₂Cl₂, the organic phase is washedwith a NaHCO₃ saturated solution, then with a NaCl saturated solutionand dried over Na₂SO₄. After removal of the solvent, the residue ispurified by chromatography on a silica gel column (eluent hexane/AcOEt9:1) to obtain 175 mg (89%) of the carbonate.

13-Dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatin III1,14-carbonate, amorphous white solid. IR (KBr) 1834, 1771, 1735, 1709,1232, 1103, 1010, 854 cm⁻¹.

¹H NMR (200 MHz, CDCl₃): δ=8.03 (Bz AA′), 7.60 (Bz, C), 7.50 (Bz, BB′),6.52 (s, H-10), 5.92 (d, J=6.7 Hz, H-2), 5.70 (br t, J=8.0 Hz, H-7),4.95 (br d, J=8.2 Hz, H-20b), 4.77 (s, H-14), 4.02 (d, J=6.7 Hz, H-3),2.71 (m, H-6), 2.29 (s, OAc), 1.96 (s, H-18), 1.27-1.01 (m, H-16, H-17,H-19).

EXAMPLE VIII Preparation of 14β-hydroxy-10-deacetylbaccatin III1,14-carbonate

A solution of 13-dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatinIII 1,14-carbonate (500 mg) in MeOH (8 ml) is cooled to 0° C. on icebath and added with solid NaBH₄ (44 mg) in 5 min. The mixture is stirredat r.t. for 1 h, then cooled to 0° C. Acetone is added (2 ml) in 5 min,the mixture is concentrated, then added with AcOEt (10 ml) and filteredthrough Celite. The clear solution is washed with a NaCl saturatedsolution and dried over Na₂SO₄. The solvent is evaporated off to give aresidue (4.5:1 mixture of C13 epimers) which is purified bychromatography on a silica gel column (eluent hexane/AcOEt 1:1) toobtain 251 mg of the 13β epimer and 55 mg of the 13α epimer (88% total)of the deprotected carbonate.

13α-14β-hydroxy-10-deacetylbaccatin III 1,14-carbonate. amorphous whitesolid. IR (KBr): 3520 (OH), 1834, 1709, 1232, 1103, 1010, 854 cm⁻¹.

¹H NMR (200 MHz, CDCl₃): δ=8.03 (Bz AA′), 7.60 (Bz, C), 7.50 (Bz, BB′),6.27 (s, H-10), 5.92 (d, J=6.7 Hz, H-2), 4.95 (br d, J=8.2 Hz, H-20b),4.85 (m, H-13), 4.77 (s, H-14), 4.42 (br t, J=8.0 Hz, H-7), 4.02 (d,J=6.7 Hz, H-3), 2.71 (m, H-6), 2.29 (s, OAc), 1.96 (s, H-18), 1.27-1.01(m, H-16, H-17, H-19). 13α-14β-hydroxy-10-deacetylbaccatin III1,14-carbonate, amorphous white solid. IR (KBr): 3520 (OH), 1834, 1709,1232, 1103, 1010, 854 cm⁻¹.

¹H NMR (200 MHz, CDCl₃): δ=8.03 (Bz AA′), 7.60 (Bz, C), 7.50 (Bz, BB′),6.27 (s, H-10), 5.92 (d, J=6.7 Hz, H-2), 4.95 (br d, J=8.2 Hz, H-20b),4.80 (m, H-13), 4.77 (s, H-14), 4.42 (br t, J=8.0 Hz, H-7), 4.02 (d,J=6.7 Hz, H-3), 2.71 (m, H-6), 2.29 (s, OAc), 1.96 (s, H-18), 1.27-1.01(m, H-16, H-17, H-19).

1. A compound selected from the group consisting of:7,10-bistrichloroacetyl-10-deacetylbaccatin III,13-dehydro-14β-hydroxy-10-deacetylbaccatin III,13-dehydro-14β-hydroxy-7-triethylsilylbaccatin III,1,14-carbonate-13-dehydro-7-triethylsilylbaccatin III,1,14-carbonate-7-O-triethylsilylbaccatin III,13-dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatin III1,14-carbonate.
 2. The compound according to claim 1, wherein saidcompound is 7,10-bistrichloroacetyl-10-deacetylbaccatin III.
 3. Thecompound according to claim 1, wherein said compound is13-dehydro-14β-hydroxy-10-deacetylbaccatin III.
 4. The compoundaccording to claim 1, wherein said compound is13-dehydro-14β-hydroxy-7-triethylsilylbaccatin III.
 5. The compoundaccording to claim 1, wherein said compound is1,14-carbonate-13-dehydro-7-triethylsilylbaccatin III.
 6. The compoundaccording to claim 1, wherein said compound is1,14-carbonate-7-O-triethylsilylbaccatin II.
 7. The compound accordingto claim 1, wherein said compound is13-dehydro-14β-hydroxy-7,10-bistrichloroacetyl-baccatin III1,14-carbonate.